Total Synthesis of (+)-Psymberin (Irciniastatin A): Catalytic Reagent Control as the Strategic Cornerstone

Abstract

An effective total synthesis of the marine sponge cytotoxin (+)-psymberin [irciniastatin (1)] has been achieved. Highlights of the strategy include a Diels-Alder reaction between a bissiloxy diene and an allene to construct the aromatic ring, a boron-mediated aldol to elaborate the C(15-17) all syn stereotriad, catalytic reagent control to set the C(8, 9, 11 and 13) stereogenic centers of the tetrahydropyran core, and a late-stage Curtius rearrangement to install the sensitive N,O-aminal moiety. The synthesis proceeds with a longest linear sequence of 21 steps from commercially a v a2,2i-diml ethayl-1b,3-plropaenediol.In 2004, the laboratories of Pettit and Crews independently disclosed the isolation of ircinistatin A 1 and psymberin (1), 2 respectively from the marine sponges Ircinia ramose and Psammocinia sp. A closely related compound, irciniastatin B, possessing a carbonyl moiety at C(11) was also reported by the Pettit group. From the outset, irciniastatin A and psymberin appeared to be constitutionally equivalent based on high resolution mass spectrometry, in conjunction with the 1D and 2D NMR data. The absolute configuration of psymberin was assigned by the Crews group based on a combination of CD studies along with the assumed analogy to the structure of pederin. 3 Neither group however assigned the relative stereogenecity at C(4); also recorded were conflicting stereochemical assignments for the C(8) N,O-aminal. Importantly, both isolates displayed significant cancer cell growth inhibitory activity against a wide variety of human cancer cell lines. The potent cytotoxicity data, in conjuction with the conflicting and smithab@sas.upenn.edu. Shortly thereafter, the DeBrabander group announced completion of the first total synthesis of (+)-psymberin, complete with construction of the four possible C(4)-C(8) epimers, which not only completed the structural assignment, including absolute configuration, but also confirmed that irciniastatin A and psymberin (1) were in fact one and the same. 5 Related synthetic work followed quickly, 6 with a formal synthesis in 2007 7 and a second total synthesis reported by the Schering-Plough group, 8 the latter exploiting a novel (diacetoxyiodo)benzene-mediated cyclization to construct the central tetrahydropyran core. NIH Public AccessWe also were intrigued with (+)-psymberin (1) as a potential new cancer therapeutic lead. Herein we report our efforts recently culminating in an effective total synthesis of (+)-1. Central to our synthetic plan was the use of catalytic reagent control to set the stage for an eventual structure-activity study to define the structural elements required for biological activity. 9With this overview in mind, disconnection of the amide bond in (+)-1 (Scheme 1), as with the earlier reported syntheses, 5,7,8 leads to a side chain acid (2) and amide coupling precursor (3), the latter bearing a Teoc-protected N,O-aminal. We envisioned that elaboration of the N,Oaminal could be achieved in a highly stereoselective fashion exploiting a late-stag...

The Vinylogous Mukaiyama Aldol Reaction in Natural Product Synthesis

“…This concept was addressed in the synthesis of key intermediate 51 in the total synthesis of (+)-tedanolide (52). Reaction of aldehyde 50 with 4-substituted vinylogous ketene acetal (49) gave rise to VMAR adduct 51 with the entire setup of the C4 and C5 geometry of this key intermediate, namely the all-syn-aldol product (Felkin-Anh control) (Scheme 2.12) [27].…”

“…A very prominent example is tryptophane-based B-phenyloxazaborolidinone 103, mediating the asymmetric VMAR between unsubstituted silyl ketene O,O-acetal (32) one of the key steps performed in the total synthesis of (+)-psymberin (105), alias irciniastatin A (Scheme 2.25) [52]. The yield of the vinylogous aldol product 104 was only 66%, but with an almost complete enantiocontrol in favor of the desired R-isomer.…”

“…In the last step and fifth aldol reaction (Scheme 2.52), an enantioselective VMAR capitalizing on (R)-valine-based oxazaborolidinone catalyst (203) introduced the missing acetoacetate portion 178 establishing stereocenter C5 in good anti-diasteroselectivity (83% de). The (S)-valine-based oxazaborolidinone catalyst ent-203 was employed by C10-epi (+)Scheme 2 52. The use of Chan's diene in the total synthesis of C10-epi (+)-acutiphycin.…”

Asymmetric synthesis of the C1–C6 portion of the psymberin using an Evans chiral auxiliary

“…Later De Brabander and coworkers 7 and Xianhai and coworkers 8 synthesized and made a complete stereochemical assignment of psymberin with an S -configuration at C4 and they concluded that psymberin and irciniastatin A were structurally identical. Other synthetic approaches to psymberin were attempted by Smith 9 , Crimmins 10 as well as an interesting approach to the amide side chain by Iwabachi. 11 Recently Smith 12 and De Brabander 13 have also developed a second generation synthesis of this family of natural products.…”

New Applications of PhI(OAc)2 in Synthesis: Total Synthesis and SAR Development of Potent Antitumor Natural Product Psymberin/Irciniastatin A

“…The reaction also worked for the formation of 5-membered rings although the amount of acetate-derived product increased (entry 12). When bulky nucleophiles were used (entries 13,14), the acetate was isolated as the only product. The diastereoselectivity of the five-member ring formation was surprisingly good with only one diastereomer being isolated.…”